Long-term mystery on muscle mechanisms may be solved, and may lead to better drugs

Long-term mystery on muscle mechanisms may be solved, and may lead to better drugs
Modeling of Pi-release of striated muscle (cardiac) myosin II. a Schematic illustration of Pi-release from myosin subfragment 1: with binding of ATP (1), Pi-binding to the active site (2) Pi-binding to the secondary site (3) release via the back door and finally weak electrostatic binding to surface sites (4) on the myosin head. The location of Pi in well-defined positions is indicated by solid spheres. Arrows indicate the routes of Pi from ATP binding to release via the back door and its weak binding on the motor surface. The orange dashed box indicates part of subfragment 1 shown in (b). b Structure of the myosin II motor domain in the pre-powerstroke state (left; PDB code 5N6A (Pre-powerstroke)) and molecular model (right) of a Pi-release state generated from the 5N6A (Pre-powerstroke)structure by using the switch II conformation from myosin VI (PDB 4PFO (Pi-release state)). Analysis of the available space in the structure (using the HOLE computer program) indicated that, in the pre-powerstroke state, the Pi-release path via the back door is closed (red patches). In contrast, this path is fully open in the modeled Pi-release state (green and blue; see Methods). The red box indicates the region shown in detail in c. Actin binding site is indicated as well as the direction (arrow) where the essential (ELC) and regulatory light chain (RLC) are found. c Structural model of myosin II in our modeled Pi-release state (b; right, red box) with phosphate in the secondary site (orange). The position of Pi in the active site in the pre-powerstroke state is also indicated (beige). To allow the release of the phosphate, Switch II (orange wire) has moved from its initial pre-powerstroke state to the modeled state shown. Switch I shown in purple. d Electrostatics around the opening of the back door in myosin II (PDB: 5N6A (Pre-powerstroke)). The surface is colored according to its surface electrostatic potential, from −2.0 kBT (deep red) to +2.0 kBT (deep blue). Credit: Nature Communications (2022). DOI: 10.1038/s41467-022-32110-9

New knowledge about the very smallest muscle components, myosin and actin, can contribute to more effective treatment methods for heart and muscle diseases. Together with a research group from Canada, researchers at Linnaeus University have come up with answers that have eluded the research community for decades.

The question concerning what happens at the molecular level in our muscles when they are activated has kept researchers occupied for decades. In our muscles, there are billions of small proteins called myosin and actin. The size of each of them being only one-hundred-thousandth of a millimeter.

These microscopic units create by converting cell fuel to, among other things, phosphate. However, exactly what this process looks like has been debated for a long time.

"When some of my colleagues and I wrote a review article on the subject in 2015, we noted that the number of hypotheses seems to be almost as high as the number of researchers," says Alf Månsson, professor of physiology at Linnaeus University.

Several new answers

The new research from Linnaeus University provides a number of answers to what happens at the in our muscles when they are activated. The study that was recently published in the journal Nature Communications was conducted together with a research group from McGill University in Montreal, Canada.

"The results are of great potential significance for the treatment of serious diseases where myosin plays a key role. In addition to serious diseases in the heart and body muscles, this applies to the spread of cancer cells to new tumors and to the invasion of human red blood cells by malaria parasites," Månsson explains.

More specifically, the researchers have mapped out how phosphate, the substance that is created when our muscles are activated, behaves when it is released from the myosin at contractions. The researchers present evidence that phosphate moves in a different way than what was previously thought, and it makes more "pauses" in and on the myosin molecule.

Requires special microscopes

Through these new discoveries, the researchers can explain phenomena for which earlier models have provided contradictory results. The achievements were made possible by combining calculation-based computer modeling with experimental studies of individual myosin molecules in a laboratory environment.

"These molecules are so small that they cannot be seen using regular optical microscopes. However, with the help of atomic force microscopy it is possible to observe an individual myosin molecule in motion," Månsson continues.

More effective drugs

The findings are of significance for the development of future drugs linked to heart and muscle diseases. The question concerning how myosin behave has become a key issue here. Detailed knowledge about the functioning of makes it possible to adapt drugs to this detailed function to give them the desired effect.

"We hope that our findings will pave the way for new ideas in this respect as well as further fine-tuning of already existing medicines," Månsson concludes.

The article, "Multistep orthophosphate release tunes actomyosin energy transduction," is published in Nature Communications.

Explore further

New knowledge of the muscular system important for future treatment of diseases

More information: Luisa Moretto et al, Multistep orthophosphate release tunes actomyosin energy transduction, Nature Communications (2022). DOI: 10.1038/s41467-022-32110-9
Journal information: Nature Communications

Citation: Long-term mystery on muscle mechanisms may be solved, and may lead to better drugs (2022, August 10) retrieved 25 September 2022 from https://phys.org/news/2022-08-long-term-mystery-muscle-mechanisms-drugs.html
This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.

Feedback to editors